DE2760005C2 - Optically active norpinene and process for their preparation - Google Patents

Description

(D

where Ri denotes acetoxy or forms a double bond together with the substituent R3, R2 denotes acetoxy or forms a double bond together with the substituent R3 and R3 forms a double bond together with the substituent Ri or together with the substituent R ₂

2. (+) - 6,6-Dimethyl-2 ^ -diacetoxy-3-norpinene.

3. (- -) -6,6-Dimethyl-2,4-diacetoxy-2-norpinene.

4. A method for producing an optically active norpinene according to claim 1, characterized in that that an optically active nopinonenol acetate of the general formula II

H-,

01)

with lead tetraacetate in a non-reactive organic solvent.

Certain 1-hydroxy-S-substituted-ö, e-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-ones are interesting active pharmaceutical ingredients because they affect the central nervous system of mammals. A dl mixture of such compounds in which the hydrogen atoms present in positions 6a and 10a are oriented towards each other in trans position, is particularly suitable for the treatment of anxiety states and depression and painful conditions. The use of these compounds for the stated purpose is described in US Pat 39 53 603, 39 28 598 and 39 44 673 described, with particular reference to the use of the dl racem mixture of 6a, 10a-trans-1-hydroxy-3- (l, l-dimethylheptyl) -6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] py - ran-9-on is referenced by the generic name Nabilon.

A separation of the dl raceme mixture of the cis and trans isomers of the above hexahydrodibenzopyranones in the corresponding optically active isomers has to be compounds with different biological Properties led. One of the optical isomers of cis- and trans-hexahydrodibenzopyranones appears here in particular to be more effective than the other optical isomer in terms of its impact on the mammalian central nervous system.

The separation of a corresponding dl race mixture However, in the respective optically active isomers is not very economical, and there are also So far no satisfactory process through which 'optically active isomers of certain cis and trans-1-hydroxy • 3-substituted-6,6-dimethyl-

have it manufactured directly. The object of the invention is therefore to provide means and ways by which such optically active hexahydrodibenzopyranones can be produced directly in an economical manner, and this object is now achieved according to the invention by the optically active norpinenes of the general given Formula I and the process for their preparation solved.

The compounds of the formula I according to the invention are valuable intermediates for the preparation an optical isomer of a hexahydrodibenzopyranone of the general formula III

OH

(ΠΙ)

CH,

where the hydrogen atoms present at positions 6a and 10a are either in the cis or trans conformation and R _{4 stands} for Ci-Co-alkyl, C-Cio-alkenyl, O-Cn-cycloalkyl or Cs-Cn-cycloalkenyl stands by having an optically

active norpinanone of the general formula IV O

αν)

OH

wherein R4 has the above meaning with an acid implemented, whereby the norpinanone of the, which is required as a starting material and is also new Above formula IV can be prepared by an inventive optically active norpinen Formula I with a resorcinol of the general formula V

HO

(V)

wherein R4 has the above meaning in the presence of a Reacts acid in a non-reactive organic solvent.

A preferred process for the preparation of hexahydrodibenzopyranones of the formula! II is in that an optically active 4- (4-substituted-2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone of formula IV with a protic acid in a non-reactive organic solvent to form a optical isomer of a 6a, lOa-cis-1-hydroxy-3-substituted

benzo [b, d] pyran-9-one converts.

Another preferred process for the preparation of hexahydrodibenzopyranones of the formula III consists in that an optically active 4- (4-substituted-2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone of formula IV with a Lewis acid in a non-reactive organic solvent in a optical isomer of a 6a, 10a-trans-1-hydroxy-3-substituted-6,6-dimethyl-6,6a, 7,8,10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one convicted. Lewis acids particularly preferred for this purpose are tin (IV) chloride and boron trifluoride and aluminum chloride.

After a very besonoers preferred process for preparing Hexahydrodibenzopyranonen of the formula III is a (+) -4- [4- (C ₅ -C | ₀ -AlkyI) -2,6-dihydroxyphenyl] -6,6-dimethyl-2 -norpinanone with

Tin (IV) chloride, whereby the corresponding (-) - 6a, 10a-trans-1-hydroxy-3- (C ₅ -C, o-alkyl) -6.6-dimethyl-6,6a, 7,8, 10,10a-hexahydro-9H-dibenzo [b, d] pyran-9-one is obtained.

In the compounds of the above formula I, only one of the substituents Ri or R _{2 is} acetoxy, so that the other of the substituents R or R ₂ together with the substituent R _{3 forms} a double bond.

The optically active norpinenes of the general formula I according to the invention can - as already stated - be prepared by reacting an optically active nopinonenol acetate of the general formula II with lead tetraacetate. 23, 1069 (1970) described methods. Such compounds are derived from the corresponding optically active d- and 1-isomers of ß- pinene.

The norpinenes of the general formula I according to the invention are best prepared by reacting the nopinonenol acetate of the general formula II with excess lead tetta acetate in a non-reactive organic solvent, preferably benzene however, an even larger excess can also be used. The reaction is normally ^{carried out at 50 to 100 °} C., and the duration of the reaction time determines the product obtained in each case

Terminated the reaction after 1 to 3 hours, is then obtained, after appropriate isolation as Produkv an optically active isomer of 6,6-dimethyl-2,2-diacetoxy-i-norpinen, wherein Ri is acetoxy and the substituents R ₂ and R3 together form a double bond. If, on the other hand, the reaction is allowed to run for 16 to 20 hours, the product is an optical isomer of 6,6-dimethyl-2,4-diacetoxy-2-norpinene, in which Ri together with R 3 represents a double bond and R _{2 represents} acetoxy stands. The reaction product is isolated in each case by filtering the reaction mixture and distilling the filtrate.

This process converts a (-) - nopinonenol acetate of the general formula II into a (-) - 2,4-diacetoxy-2-norpinene or a (+) -2,2-Dia ': etoxy-3-norpinene of the general formula I converted. Comes the other way round there is therefore also a conversion of a (Η -) - compound of the general formula II into a (+) -2,4-diacetoxy compound or into a (-) - 2,2-diacetoxy compound of the general formula I.

The optically pure isomers of 6, b-dimethyl-2,4-diacetoxy-2-norpinene and 6,6-dimethyl-2,2-diacetoxy-3-norpinen of the general formula I are with an in Position 5 substituted resorcinol of the general formula V further-implemented, whereby one optically pure 4- (4-substituted-2,6-dihydroxyphenyl) -6,6-dimethyl-2-norpinanone of the general formula IV is obtained.

The preparation of a (+) compound of the formula IV takes place starting from a (-) -2,4-diacetoxy-2-norpinene or from a (-t -) - 2,2-diacetoxy-3-norpinene of the general formula I. The opposite is used to produce a (-) compound of the general formula IV therefore either from a (+) -2,4-diacetoxy-2-norpinene or according to the invention from a (-) - 2,2-diacetoxy-3-norpine of the general formula I according to the invention.

The invention is illustrated by the following examples.

example 1

(-) -6,6-Dimethyl-2,4-diacetoxy-2-norpinene
A solution of 18.0 g kept under nitrogen

(-) -Nopinonenol acetate in 250 ml dry benzene 48.8 g of lead tetraacetate are added while stirring in an amount, which is previously over vacuum Has dried phosphorus pentoxide and potassium hydroxide. The reaction mixture is brought to reflux temperature heated and stirred for 18 hours. The reaction mixture is then cooled to room temperature and filtered The filtrate is washed with 10 percent strength aqueous sodium bicarbonate solution and with water and dried by subsequent removal of the solvent by evaporation under reduced pressure 23.5 g of crude product are obtained under pressure in the form of a clear liquid. The subsequent distillation of this Product leads to 9.3 g (-J-ö ^ -Dimethyl ^^ - diacetoxy-2-norpinen, that under a pressure of 5 Torr at 115 1 · -, boils up to 118 ° C

[«]» = -89.7 ° (C = I ₁ O ₁ CHCl ₃ ).

H 'NMR (CDCl ₃₎ delta 5.25 (m. 2H) delta 2.4 (m, 4H) delta 2.1 (s, 3H) delta 2.0 (s, 3H) delta 1.35 (S ₁ 3H) delta 1.0 (s, 3H)

IR (CHCl ₃ ): 1730.1763 cm- ', carbonyl. Measurement spectrum m / e: 196 (M + - CH ₂ = C = O).

Example 2 (+) -6, <i-Dimethyl-2,2-diacetoxy-3-norpinene

A solution of 18.0 g of (-) - nopinonenol acetate in 250 ml of dry benzene, kept under nitrogen, is admixed with stirring in an amount with 48.8 g of lead tetraacetate which has previously been dried under vacuum over phosphorus pentoxide and potassium hydroxide. The reaction mixture is heated to reflux temperature and stirred for 2 hours. The reaction mixture is then cooled to room temperature, washed with aqueous sodium bicarbonate solution and with water and dried. Subsequent evaporation of the solvent under reduced pressure gives an oil. The subsequent distillation of this oil yields 9.8 g of (+) -6,6-dimethyl-2,2-diacetoxy-3-norpinen boiling under a pressure of 5 Torr at 102-103 ⁰ C.

[λ] f = + 33.2 ° (C = 1.0, CHCl ₃ ).

Analysis for Ci ₃ HisO4:

Calculated: C 65.53; H 7.61; COCH ₃ 36.12; found: C, 65.77; H 7.32; COCH ₃ 36.56.

H ¹ NMR (CDCl ₃ ) delta 6.4 (m, 2H) delta 3.15 (m, IH) delta 2.3 (m, 3H) delta 2.1 (s, 6H) delta 1.4 (s, 3H) delta l, l (s, 3H)

Mass spectrum m / e: 196 (M + - 42).

IR (CHCl ₃ ) 1750 cm ^-1 , carbonyl.

30th

Claims (1)

1 claims: 1. Optically active norpinen of the general formula I CH ₃ CO R ₁ Η — ι - R3